We are proposing studies utilizing the patients enrolled in the DMID-funded Randomized, Double-Blind Trial of Clindamycin, Trimethoprim-Sulfamethoxazole, or Placebo for Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA). This contract by NIAID to the Co-PI at the University of Chicago as well as investigators at the University of California/San Francisco, Harbor-University of California/Los Angeles, has provided a unique opportunity to explore unaddressed issues. About 375 children and adults with skin and soft tissue infections (SIs) will be enrolled for a period of three years at the University of Chicago. Preliminary data indicate that about 84% of enrollees will have a S. aureus SI, providing a unique opportunity to perform additional research addressing the underlying cause for increased susceptibility to SIs in the general population. In the last decade the incidence and frequency of MRSA infections has increased exponentially, particularly among otherwise healthy individuals, to the extent that CA-MRSA has become epidemic in the US and is now a public health imperative. The recognition that CA-MRSA strains can both spread rapidly and cause severe disease mandates a need for urgent investigation to understand the molecular microbial pathogenicity and underlying host immune responses. Accordingly, we have assembled a multidisciplinary team of microbiologists, infectious disease experts, and immunologists to explore simultaneously several areas likely to yield important insights into the biology of the CA-MRSA epidemic, with a focus on the role of host immune responses in CA-MRSA infection. Studies detailed in this proposal will provide substantial insight into the contributions of host innate and adaptive mechanisms to infection susceptibility. It is hoped that new information will guide novel therapeutic and preventive strategies to combat CA-MRSA infection.